Neurodegeneration in Alzheimer's disease (AD) is associated with the accumulation of extracellular plaques of small peptides, called amyloid-β (Aβ), and intracellular neurofibrillary tangles, comprising aggregates of hyperphosphorylated tau protein (1). Evidence suggests that inflammatory events are involved in the pathogenesis of AD. Pro-inflammatory molecules are present at sites of Aβ plaques and anti-inflammatory drugs slow the progression of the disease (2-4).
Cells of the brain respond to ischemia and increased concentrations of Aβ by generating pro-inflammatory mediators, such as TNFα, 1β, and prostanglandins. The production of these inflammatory factors is regulated by nuclear factor kappa B (NF-κB), a transcription factor that is widely expressed in the nervous system. NF-κB immunoreactivity is elevated in regions of neuronal plaques in AD patients, suggesting that NF-κB pathways may be activated in AD brains (5). Aβ peptides have been shown to activate NF-κB in primary neurons and astrocytes (6). Studies have shown that anti-inflammatory drugs, such as indomethacin, can reduce the level of Aβ peptides and NF-κB in the brains of the transgenic mouse model of AD (TG2576) (7). Cell culture systems further suggest that a wide array of NF-κB inhibitors may be able to block the formation of Aβ(5). NF-κB inhibitors are therefore believed to have therapeutic importance in the treatment of AD patients, by both blocking inflammatory processes and the formation of Aβ.
Linoleic acid phospholipids, such as dilinoleoylphosphatidylcholine (DLPC), have been shown to regulate the hepatic production of HDL, through effects on mitogen-activated protein kinase (MAPK) and PPARα(8,9). An inverse relationship between inflammation and plasma HDL levels has long been recognized (10,11) and studies suggest that some HDL therapeutics may directly act as anti-inflammatory compounds (12,13). DLPC directly reduces alcohol-induced hepatic inflammatory cascades in experimental animal and cellular models (14-16) and studies show that PC can also inhibit TNF-α-induced inflammatory responses in model human intestinal cells, CaCO-2 (17).
Phospholipids (PL) are important components of the human body and constituents of the circulating plasma lipoproteins. PL have been suggested to have therapeutic value in treating inflammatory and neurodegenerative diseases (18,19,26,27). PL have been shown to have anti-inflammatory effects in both the liver and intestinal track (17,28). PL protect against alcoholic liver injury (14,27,28) and have also been shown to be effective at alleviating gastrointestinal inflammation caused by ulcerative colitis (29). Other studies have shown therapeutic value of PL for both Alzheimer's Disease (AD) and other neurological diseases (18,19). PL have shown the potential to improve memory and cognitive function in rodents (30-32) and PL have also been used for treating senile dementia and other neurodegenerative disorders in humans (20-24).
The inventors have previously shown that the acyl chain composition of PL directly impact cellular signaling and transcriptional processes (8,9). Soy PL are enriched in the linoleic fatty acid, linoleic acid, an 18 carbon acyl chain with 2 unsaturations (18:2). Linoleic PL act through MAPK and PPARα pathways to stimulate hepatic HDL/apoA-I secretion and raise plasma HDL levels (8,9,33). Decreased plasma HDL and apoA-I levels are highly correlated with the severity of AD (34,35). Niacin also acts through MAPK and PPARα and has been shown to have both HDL raising therapeutic value as well as anti-inflammatory properties (12,13). Dietary niacin may also directly protect against AD and age related cognitive decline (36).
There is a need in the art for novel anti-inflammatory compositions. Further, there is a need in the art for novel compositions comprising linoleic phospholipids. Also, there is a need in the art for novel methods and for inhibiting inflammatory pathways and/or neurodegenerative processes.